1-237885843-G-A

Position:

• chr1-237885843-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_021186.5(ZP4):​c.883C>T​(p.Pro295Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00535 in 1,614,110 control chromosomes in the GnomAD database, including 354 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.027 (190 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (164 hom.)
• Consequence: ZP4 NM_021186.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.95

Genes affected

ZP4 (HGNC:15770): (zona pellucida glycoprotein 4) The zona pellucida is an extracellular matrix that surrounds the oocyte and early embryo. It is composed primarily of three or four glycoproteins with various functions during fertilization and preimplantation development. The nascent protein contains a N-terminal signal peptide sequence, a conserved ZP domain, a consensus furin cleavage site, and a C-terminal transmembrane domain. It is hypothesized that furin cleavage results in release of the mature protein from the plasma membrane for subsequent incorporation into the zona pellucida matrix. However, the requirement for furin cleavage in this process remains controversial based on mouse studies. Previously, this gene has been referred to as ZP1 or ZPB and thought to have similar functions as mouse Zp1. However, a human gene with higher similarity and chromosomal synteny to mouse Zp1 has been assigned the symbol ZP1 and this gene has been assigned the symbol ZP4. [provided by RefSeq, Jul 2008]

ENSG00000237250 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003302455).
• BP6: Variant 1-237885843-G-A is Benign according to our data. Variant chr1-237885843-G-A is described in ClinVar as [Benign]. Clinvar id is 773297.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.089 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZP4	NM_021186.5	c.883C>T	p.Pro295Ser	missense_variant	7/12	ENST00000366570.5	NP_067009.1
LOC100130331	NR_027247.2	n.410+3275G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZP4	ENST00000366570.5	c.883C>T	p.Pro295Ser	missense_variant	7/12	1	NM_021186.5	ENSP00000355529.4
ENSG00000237250	ENST00000450451.1	n.410+3275G>A		intron_variant		1
ZP4	ENST00000611898.4	c.883C>T	p.Pro295Ser	missense_variant	7/13	5		ENSP00000482304.1

Frequencies

GnomAD3 genomes AF: 0.0269 AC: 4093 AN: 152106 Hom.: 189 Cov.: 32

Gnomad AFR AF: 0.0915

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0136

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.0234

GnomAD3 exomes AF: 0.00734 AC: 1846 AN: 251468 Hom.: 63 AF XY: 0.00542 AC XY: 737 AN XY: 135916

Gnomad AFR exome AF: 0.0933

Gnomad AMR exome AF: 0.00544

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000756

Gnomad OTH exome AF: 0.00603

GnomAD4 exome AF: 0.00310 AC: 4528 AN: 1461886 Hom.: 164 Cov.: 32 AF XY: 0.00271 AC XY: 1972 AN XY: 727246

Gnomad4 AFR exome AF: 0.0966

Gnomad4 AMR exome AF: 0.00608

Gnomad4 ASJ exome AF: 0.00119

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000185

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.000398

Gnomad4 OTH exome AF: 0.00768

GnomAD4 genome AF: 0.0269 AC: 4101 AN: 152224 Hom.: 190 Cov.: 32 AF XY: 0.0258 AC XY: 1919 AN XY: 74416

Gnomad4 AFR AF: 0.0915

Gnomad4 AMR AF: 0.0135

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000603

Gnomad4 OTH AF: 0.0232

Alfa AF: 0.00638 Hom.: 54

Bravo AF: 0.0311

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0892 AC: 393

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.00894 AC: 1085

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.00109

EpiControl AF: 0.00119

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 06, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T;T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.79	T;.
MetaRNN	Benign	0.0033	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.1	M;M
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-6.8	.;D
REVEL	Benign	0.25
Sift	Benign	0.050	.;D
Sift4G	Uncertain	0.041	D;D
Polyphen		1.0	D;D
Vest4		0.53
MVP		0.80
MPC		0.11
ClinPred		0.082	T
GERP RS		4.8
Varity_R		0.48
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs34811980; hg19: chr1-238049143;